Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration

被引：129

作者：

Curtis, James ^{[1
]}

Luo, Yang ^{[2
]}

Zenner, Helen L. ^{[1
]}

Cuchet-Lourenco, Delphine ^{[1
]}

Wu, Changxin ^{[1
]}

Lo, Kitty ^{[3
]}

Maes, Mailis ^{[1
]}

Alisaac, Ali ^{[1
]}

Stebbings, Emma ^{[1
]}

Liu, Jimmy Z. ^{[2
]}

Kopanitsa, Liliya ^{[1
]}

Ignatyeva, Olga ^{[4
]}

Balabanova, Yanina ^{[5
,6
,7
]}

Nikolayevskyy, Vladyslav ^{[6
,7
,8
]}

Baessmann, Ingelore ^{[9
]}

Thye, Thorsten ^{[10
]}

Meyer, Christian G. ^{[10
]}

Nuernberg, Peter ^{[9
,11
,12
]}

Horstmann, Rolf D. ^{[10
]}

Drobniewski, Francis ^{[6
,7
,8
]}

Plagnol, Vincent ^{[3
]}

Barrett, Jeffrey C. ^{[2
]}

Nejentsev, Sergey ^{[1
]}

机构：

[1] Univ Cambridge, Dept Med, Cambridge CB2 2QQ, England

[2] Wellcome Trust Sanger Inst, Hinxton, Cambs, England

[3] UCL, Genet Inst, London, England

[4] Samara Oblast TB Dispensary, Samara, Russia

[5] Robert Koch Inst, Berlin, Germany

[6] Univ London Imperial Coll Sci Technol & Med, London, England

[7] Queen Mary Univ London, London, England

[8] Publ Hlth England Natl Mycobacterium Reference La, London, England

[9] Univ Cologne, Cologne Ctr Genom, D-50931 Cologne, Germany

[10] Bernhard Nocht Inst Topical Med, Dept Mol Med, Hamburg, Germany

[11] Univ Cologne, Ctr Mol Med Cologne, D-50931 Cologne, Germany

[12] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-50931 Cologne, Germany

来源：

NATURE GENETICS | 2015年 / 47卷 / 05期

基金：

英国惠康基金; 欧洲研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; GENOTYPE IMPUTATION; IMMUNE-RESPONSE; ARF GAPS; ARCHITECTURE; EXPRESSION;

D O I：

10.1038/ng.3248

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Human genetic factors predispose to tuberculosis (TB). We studied 7.6 million genetic variants in 5,530 people with pulmonary TB and in 5,607 healthy controls. In the combined analysis of these subjects and the follow-up cohort (15,087 TB patients and controls altogether), we found an association between TB and variants located in introns of the ASAP1 gene on chromosome 8q24 (P = 2.6 x 10(-11) for rs4733781; P = 1.0 x 10(-10) for rs10956514). Dendritic cells (DCs) showed high ASAP1 expression that was reduced after Mycobacterium tuberculosis infection, and rs10956514 was associated with the level of reduction of ASAP1 expression. The ASAP1 protein is involved in actin and membrane remodeling and has been associated with podosomes. The ASAP1-depleted DCs showed impaired matrix degradation and migration. Therefore, genetically determined excessive reduction of ASAP1 expression in Mycobacterium tuberculosis-infected DCs may lead to their impaired migration, suggesting a potential mechanism of predisposition to TB.

引用

页码：523 / U128

页数：7

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